CLINICAL NEURO-MODULATION

NERVOUS SYSTEM BALANCING IN INTEGRATIVE MEDICINE &

CLINICAL NEUROPSYCHIATRY

Desiderio Pina, MD, MPH, LFACPMedical Director

Springboro Medical Wellness&

Neuropsychiatric Center

www.healingbodyandminds.comDrPina_MedWellness@me.com

๏ Grant/Research Support:

๏ Wright State University, Boonshoft School of Medicine (WSU-BSM)

๏ NSF

๏ DARPA

๏ WHO / UNICEF

๏ Consultant/Advisory Board:

๏ Medical Wellness & Neuropsychiatric Center

๏ Speaker’s Bureau:

๏ NeuroRelief, Inc.

๏ PAMLABS, Inc.

๏ OTSUKA, Inc.

๏ Other Financial Support:

๏ n/a

๏ Stock/shareholder:

๏ Pfizer

๏ Johnson & Johnson

๏ ARIAD Laboratories

๏ Millennium Pharmaceuticals

๏ Patents:

๏ Non-disclosable:

๏ USAF/AFRL

๏ Human-Machine Interface

๏ Intravenous Liposomal Therapeutics

๏ Other Affiliation:

๏ WSU-BSM

๏ Dept of Pharmacology & Toxicology

๏ Dept of Psychiatry

๏ UC Dept of Psychiatry (Cincy)

๏ VA Med Ctr (Cincy)

๏ The Health Alliance (Cincy)

๏ Fort Hamilton Hospital

DISCLOSURE STATEMENTDESIDERIO PINA, MD, MPH

DISCUSSION PREVIEW

Chronic Illnesses -- Treatable but not curable...yet Integrative Medicine & Neuromodulation Psycho-neuro-endocrine-immunology Biochemically Relevant Metabolism & Physiology Neuroanatomy of Symptomatology The importance of Remission: Chronic Illness & the HPA Discuss Prevention of Damage and Reversal of Damage Risks Associated with Failure to Achieve / Sustain Remission Ideal Treatment for Complex Disorders Treatment Augmentation Neurotransmitter TESTING - NeuroScience & NeuroRelief Test then Switch? Combine? Augment? Summary Questions

A SIGN OF THE…. TIME

Anxiety

THE GOOD

THE BAD

THE UGLY

THE NERVOUS SYSTEM CONTROLS ALL BODILY

PROCESSES

BRIEF SEGWAYINTO

PSYCHO-NEURO-ENDOCRINE-IMMUNOLOGY

Galen: (2000 yrs ago) - “melancholic women are more prone to cancer [of the reproductive organs]”

Virgil: (1st Century B.C.) - “mind moves matter”

Aristotle: (400 B.C.) - “just as you ought not to attempt to use eyes without head or head without body, so you should not treat body

without soul.”

Descartes: reductionism

Sir William Osler: ‘father’ of modern medicine - believed more

important to know what was going on in a patient’s head than in his chest, to predict outcome of TB

HISTORY

PSYCHOSOMATICS

SLE Asthma ChronicPain

Chron’s Fibromyalgia CFS

IBS HIV Migraine

NEURO-IMMUNE LINKS

Immune - Neurotransmitter Links:

Brain lesions & Immune Functions

i.e. hypophysectomy

Nervous Innervation of the Immune System

i.e. ACh staining of terminals of the thymus

Effects of neurotransmitters on Immune Functions

Serotonin, Dopamine, Norepinephrine and Epinephrine, GABA, Acetylcholine, Opioids --> secreted by various immune system cells

Immune Responses to Neurotransmitters: ILs, TNF, Cytokines

SO . . .

LETS GO A BIT DEEPER. . .

BEFORE GOING BACK UP FOR AIR AND A BIGGER PICTURE

Essential AAs & Branched Chain AAs

Respiration & Ox/Redox Reactions

1-Carbon Metabolism

Niacin, Nicotinamide, NAD/NADP/NADPH

Serine

Homocysteine

Glutathione, SOD, Catalase

BIOCHEMISTRY

SAMe -- Is THE major donor of methyl groups for biosynthetic reactions.

i.e. Methylating noradrenaline to adrenaline

i.e. Phosphatidylethanolamine to phosphatidylcholine

BIOCHEMICAL REVIEW

Folate is a cofactor in one-carbon metabolism, during which it promotes the remethylation of homocysteine – a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. Dietary folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Recent epidemiological and experimental studies have linked folate deficiency and resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine in the pathogenesis of psychiatric disorders.1A better understanding of the roles of folate and homocysteine in neuronal homeostasis throughout life is revealing novel approaches for preventing and treating neurological disorders.1The present report describes the first visualization of folic acid-immunoreactive fibers in the mammalian central nervous system using a highly specific antiserum directed against this vitamin. The distribution of folic acid-immunoreactive structures was studied in the brainstem and thalamus of the monkey using an indirect immunoperoxidase technique. We observed fibers containing folic acid, but no folic acid-immunoreactive cell bodies were found. In the brainstem, no immunoreactive structures were visualized in the medulla oblongata, pons, or in the medial-caudal mesencephalon, since at this location immunoreactive fibers containing folic acid were only found at the rostral level in the dorsolateral mesencephalon (in the mesencephalic–diencephalic junction). In the thalamus, the distribution of folic acid-immunoreactive structures was more widespread. Thus, we found immunoreactive fibers in the midline, in nuclei close to the midline (dorsomedial nucleus, centrum medianum/parafascicular complex), in the ventral region of the thalamus (ventral posteroinferior nucleus, ventral posteromedial nucleus), in the ventrolateral thalamus (medial geniculate nucleus, lateral geniculate nucleus, inferior pulvinar nucleus) and in the dorsolateral thalamus (lateral posterior nucleus, pulvinar nucleus). The highest density of fibers containing folic acid was observed in the dorsolateral mesencephalon and in the pulvinar nucleus. The distribution of folic acid-immunoreactive structures in the monkey brain suggests that this vitamin could be involved in several mechanisms, such as visual, auditory, motor and somatosensorial functions.2Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency.V T Ramaekers, J Weis, J M Sequeira, E V Quadros, N Blau

Folate transport to the brain depends on ATP-driven folate receptor-mediated transport across choroid plexus epithelial cells. Failure of ATP production in Kearns-Sayre syndrome syndrome provides one explanation for the finding of low spinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) levels in this condition. Therefore, we suspect the presence of reduced folate transport across the blood-spinal fluid barrier in other mitochondrial encephalopathies. In the present patient with mitochondrial complex I encephalomyopathy a low 5-methyltetrahydrofolate level was found in the CSF. Serum folate receptor autoantibodies were negative and could not explain the low spinal fluid folate levels. The epileptic seizures did not respond to primidone monotherapy, but addition of ubiquinone-10 and radical scavengers reduced seizure frequency. Add-on treatment with folinic acid led to partial clinical improvement including full control of epilepsy, followed by marked recovery from demyelination of the brainstem, thalamus, basal ganglia and white matter. Cerebral folate deficiency is not only present in Kearns-Sayre syndrome but may also be secondary to the failure of mitochondrial ATP production in other mitochondrial encephalopathies. Treatment with folinic acid in addition to supplementation with radical scavengers and cofactors of deficient respiratory enzymes can result in partial clinical improvement and reversal of abnormal myelination patterns on neuro-imaging.3

CITE:1-Trends in NeurosciencesVolume 26, Issue 3, March 2003, Pages 137-1462-Neuroscience LettersVolume 362, Issue 3, 27 May 2004, Pages 258-2613-Neuropediatrics. 2007 Aug ;38 (4):184-7 18058625 (P,S,G,E,B,D)4-Mitochondrial diseases associated with cerebral folate deficiency.A Garcia-Cazorla, E V Quadros, A Nascimento, M T Garcia-Silva, P Briones, J Montoya, A Ormazábal, R Artuch, J M Sequeira, N Blau, J Arenas, M Pineda, V T RamaekersNeurology Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Passeig Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain; agarcia@hsjdbcn.org.5-Cerebral folate deficiency with developmental delay, autism, and response to folinic acid.P Moretti, T Sahoo, K Hyland, T Bottiglieri, S Peters, D del Gaudio, B Roa, S Curry, H Zhu, R H Finnell, J L Neul, V T Ramaekers, N Blau, C A Bacino, G Miller, F ScagliaDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.

NEUROTRANSMITTER

BASICS

NT's are classified as excitatory or

inhibitory according to the electrical &

biochemical changes induced when they

bind to their receptors

Most neurotransmitters have more than one type of receptor to which they bind and it is important to remember that different receptors can induce different changes

THE IDEAL TREATMENT FOR NEUROPSYCHIATRIC ILLNESSES

We must attempt to optimize effects on ALL POTENTIAL BIOLOGICAL SYSTEMS EARLY IN TREATMENT.

At a minimum we must attempt - -TRI-MONOAMINE MODULATION (5HT, NE, DA)

Selective serotonin increase compensatory decrease of NE and DAfatigue, a-motivation, blunted affect, cognitive impairment, sexual side effects, or “tachyphylaxis”

Use broad-spectrum AD early

Augmentation over switching

Consider possible role of nutrition-(ie folate)-related dysfunction on 5HT, NE, DA (from genetic polymorphism, illness, medication)

Consider other neurotransmitter/modulator dysfunction (glutamate, GABA, HPA-axis)

Consider psychotherapeutic interventions (especially in conjunction with pharmacotherapy)

Zajecka, John M., Goldstein, Corey & Barowski, Jeremy (2006). CHAPTER 6 - Combining Medications to Achieve Remission. Depression, 1 (1), 161-200.

FIGURE 16 CEREBRAL HEMISPHERES VI - MEDIAL VIEW

Separation of the brain in the midline (along the interhemispheric fissure) reveals the medial surface of the hemispheres, the brainstem divided, and medial view of the vermis (midline) of the cerebellum. This view of the brain and brainstem is most important for understanding the structural anatomy of the CNS.

The focus here is on the fissures, sulci and gyri which are found on the medial surface of the cerebral cortex, in the interhemispheric fissure. It should be noted that the cerebral ventricle is below (i.e. inferior to) the corpus callosum.

15 17 59

Serotonin

NorEpi

Dopamine

STRESS

TYPES OF STRESS

Stress has been described in three ways:As a stimulusAs a response to stressorsAs part of the person/environment relationship

Stress results when an individual perceives a discrepancy between the demands of a situation and his or her resources (Sarafino 2000).

GENERAL ADAPTATION SYNDROME

Perceived Stressor

Alarm Reaction

Stage of Resistance

Stage of Exhaustion

WHY ARE SOME EVENTS STRESSFUL AND OTHERS NOT?

๏ Primary Appraisal

๏ i.e. what does this mean for me?

๏Harm/loss

๏Threat

๏Challenge

๏ Secondary Appraisal

๏ i.e. how will I cope?

MEASURING STRESS

Physiological Measures

Self-Report Measures

Rating Scales

WHAT EFFECTS CAN STRESS HAVE?

Subjective effects

Behavioral effects

Cognitive effects

Physiological effects

Organizational effects

•Health effects

HEALTH EFFECTS ASSOCIATED TO STRESS

Easy Examples:

Coronary Heart Disease

Cancer

Infectious Diseases

Cognitive Impairment

ADDING LAYERS . . .

SO. . .

LETS GET STARTEDBOO !!!

FIGURE 74 THE LIMBIC LOBE

The various cortical components of the Limbic System are visualized as if one could "see through" the hemispheres. This includes the cingulate gyrus [and the cortical portions of the septal region], the parahippocampal gyrus, and the hippocampal formation - these form a border or "limbus" around the core structures of the brain.

Other structures of the limbic system are also included - the fornix, anterior commissure (a useful landmark) and the amygdala. The brainstem is also shown.

14 16 76

NEUROANATOMY OF SYMPTOMATOLOGY-1

FIGURE 16 CEREBRAL HEMISPHERES VI - MEDIAL VIEW

Separation of the brain in the midline (along the interhemispheric fissure) reveals the medial surface of the hemispheres, the brainstem divided, and medial view of the vermis (midline) of the cerebellum. This view of the brain and brainstem is most important for understanding the structural anatomy of the CNS.

The focus here is on the fissures, sulci and gyri which are found on the medial surface of the cerebral cortex, in the interhemispheric fissure. It should be noted that the cerebral ventricle is below (i.e. inferior to) the corpus callosum.

15 17 59

NEUROANATOMY OF SYMPTOMATOLOGY-2

NEUROANATOMY OF SYMPTOMATOLOGY-3

KEY COMPONENTS OF THE STRESS RESPONSE

DHEA

Epinephrine Cortisol

Adrenal Cortex

Norepinephrine

AdrenalMedulla

Two distinct parts of the adrenal gland producing both hormones and

neurotransmitters

Adrenal Cortex = cortisol and DHEA

Adrenal Medulla = norepinephrine and epinephrine

The adrenal glands secrete steroids, including some sex hormones, and catecholamines. Steroids are synthesized and secreted by the adrenal cortex, while catecholamines are synthesized and secreted by chromaffin cells of the adrenal medulla.The principal steroids are aldosterone (a mineralocorticoid) and cortisol (a glucocorticoid). Aldosterone promotes sodium retention and potassium excretion and is therefore important in maintaining fluid balance and blood pressure. Cortisol is involved in the response to stress; it increases blood pressure, blood sugar levels and suppresses the immune system.The main sex hormone secreted by the adrenals is dehydroepiandrosterone (DHEA) although is also secretes smaller quantities of other hormones chiefly: testosterone and estrogen.DHEA is the most abundant steroid in the body. It is a steroid precursor produced by the adrenal gland and converted to testosterone or the estrogens by the bodyʼs tissues. Adequate DHEA levels give the body the building blocks necessary to produce these hormones. Levels of DHEA are inversely associated with coronary artery disease. DHEA levels decrease with age.The adrenal glands secrete the catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline). Epinephrine, also known as adrenaline, is an excitatory neurotransmitter and hormone essential for lipolysis, which is a process in which the body metabolizes fat. Epinephrine is derived from the amine norepinephrine. As a neurotransmitter, epinephrine regulates attentiveness and mental focus. Epinephrine is synthesized from norepinephrine.As a hormone, epinephrine is secreted along with norepinephrine principally by the medulla of the adrenal gland. Heightened secretion can occur in response to fear or anger and will result in increased heart rate and the hydrolysis of glycogen to glucose. This reaction, referred to as the “fight or flight” response, prepares the body for strenuous activity. Epinephrine is used medicinally as a stimulant in cardiac arrest, as a vasoconstrictor in shock, as a bronchodilator and antispasmodic in bronchial asthma, and anaphylaxis. Commonly, epinephrine levels will be low due to adrenal fatigue (a pattern in which the adrenal output is suppressed due to chronic stress). Therefore, symptoms can be presented as fatigue with low epinephrine levels. Low levels of epinephrine can also contribute to weight gain and poor concentration. Elevated levels of epinephrine can be factors contributing to restlessness, anxiety, sleep problems, or acute stress.Norepinephrine is an excitatory neurotransmitter that is important for attention and focus. Norepinephrine is synthesized from dopamine by means of the enzyme dopamine beta-hydroxylase, with oxygen, copper, and vitamin C as co-factors. Dopamine is synthesized in the cytoplasm, but norepinephrine is synthesized in the neurotransmitter storage vesicles.; Cells that use norepinephrine for formation of epinephrine use SAMe as a methyl group donor. Levels of epinephrine in the CNS are only about 10% of the levels of norepinephrine. The noradrenergic system is most active when an individual is awake, which is important for focused attention. Elevated norepinephrine activity seems to be a contributor to anxiousness. Also, brain norepinephrine turnover is increased in conditions of stress. Interestingly, benzodiazepines, the primary anxiolytic drugs, decrease firing of norepinephrine neurons. This may also help explain the reasoning for benzodiazepine use to induce sleep. Norepinephrine acts as an excitatory neurotransmitter and modulates neuron voltage potentials to favor glutamate activity and neurotransmitter firing.

The General Adaptation Syndrome

1) Alarm

2) Resistance

3) Exhaustion

Figure 3.2: The General Adaptation Syndrome: Alarm Phase.

THE BODY’S RESPONSE TO STRESS

• CVD Risk increases

• Notice the hormones that are released during stressful events

• “The disease of prolonged arousal”

• Increased plaque buildup

• Hardening of the arteries

• Increased blood pressure

STRESS AND OUR HEALTH

KEY COMPONENTS OF THE STRESS RESPONSE

LC (NE)

The Locus ceruleus (LC) = a nucleus in the brain stem responsible for

physiological responses to stress and panic.

Main source of norepinephrine in the brain

The Locus ceruleus, also spelled locus caeruleus or locus coeruleus (Latin for 'the blue spot'), is a nucleus in the brain stem responsible for physiological responses to stress and panic. This nucleus is one of the main sources of norepinephrine in the brain. Melanin granules inside the LC contribute to its blue color; it is thereby also known as the nucleus pigmentosus pontis. The neuromelanin is formed by the polymerization of norepinephrine.The locus ceruleus is widely studied in relation to clinical depression, PTSD, panic disorder, and anxiety. Some antidepressant medications including Reboxetine, Venlafaxine, and Bupropion as well as Atomoxetine (ADHD) are believed on it. This area of the brain is also intimately involved in REM sleep.

KEY COMPONENTS OF THE STRESS RESPONSE

HypothalamusCorticotropin

Releasing

Factor (CRF)

Hypothalamus is the master controller of the HPA axis

(multiple ‘Releasing’ Factors)

Corticotropin-releasing hormone (CRH) aka corticotropin-releasing factor (CRF), CRH is produced in the paraventricular nucleus of the hypothalamus. CRH is carried to the anterior lobe of the pituitary, where it stimulates the secretion of corticotropin (ACTH). Release of CRH from the hypothalamus is influenced by stress, by blood levels of cortisol and by the sleep/wake cycle.

CRH receptors are also present at many different sites in the brain (eg. paraventricular nucleus, locus ceruleus and the central nucleus of the amygdala), and CRH released from nerve endings within the brain acts as a neurotransmitter.

KEY COMPONENTS OF THE STRESS RESPONSE

PituitaryAdrenal-Corticotrophic

Hormone (ACTH)

Pituitary gland has two parts that bridge the brain and body:

Anterior (FOCAL POINT FOR TODAY’S DISCUSSION)

Posterior

Adrenocorticotropic hormone (ACTH) stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also mineralcorticoids and sex steroids. ACTH is synthesized from POMC, (pro-opiomelanocortin) and secreted from the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH).

NORMAL STRESS RESPONSE

DHEA

Epinephrine Cortisol

HypothalamusAcute Stressor

Pituitary

Adrenal Cortex

Norepinephrine

Corticotropin

Releasing

Factor (CRF)

Adrenal-

Corticotrophic

Hormone (ACTH)

Cortisol

shuts off the

stress response

LC (NE)

Norepinephrine

Adrenal

Medulla

CAN TREATMENT PREVENT OR REVERSE DAMAGE?

5-HT=serotonin; NE=norepinephrine; ECT=electroconvulsive therapy.

1. Duman RS, et al. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000;48(8):732-739.

2. Sapolsky RM. Glucocorticoids and Hippocampal Atrophy in Neuropsychiatric Disorders Arch Gen Psychiatry. 2000;57(10):925-935.

STRESS1

Glucocorticoids

BDNF

Normal survival and growth

Atrophy/death of neurons

BDNF

Increased survival and growth

5-HT and NE

Glucocorticoids

??

Pharmacotherapy, ECT, psychotherapy1

Dendritic branching2

NEW

Trkb-Mediated

And now rTMS

Key PointAntidepressants may affect neuronal survival and growthBackgroundNeuronal atrophy and cell death are thought to occur as a result of hyperactivity of the stress–response system in depressed patients, which increases adrenal glucocorticoid release and decreases BDNF levels, a factor critical for the survival and function of neurons in the adult brain1The damaging effects of prolonged stress/depressive symptoms could contribute to the selective loss of volume of the hippocampus (a structure essential to learning and memory, contextual fear conditioning, and neuroendocrine regulation) observed in patients with depression. These morphologic changes have been shown to persist long after the depressive symptoms have resolved2In theory, antidepressants that affect serotonin and/or norepinephrine activity may affect neuronal survival and growth by decreasing glucocorticoid levels and increasing BDNF levels1References1. Duman RS, et al. Biol Psychiatry. 2000;48:732-739.2. Sapolsky RM. Arch Gen Psychiatry. 2000;57:925-935.

Desensitized Receptors

EARLY CHRONIC STRESS RESPONSE

Hypothalamus

Pituitary

Adrenal CortexAdrenal

Medulla

Cortisol

DHEA

Epinephrine

Norepinephrine

CRF

ACTH

Cortisol

Inhibitory

Feedback

LC (NE)

Norepinephrine

Acute stress activates the hypothalamusIncreases the release of:CRFACTHCortisol & DHEAEpinephrine & norepinephrine

Excessive cortisol binding to receptors in hypothalamus and Locus ceruleus Desensitizes cortisol receptors Starts HPA axis overdrive

Early Stage Optimal Range

DHEA 452.3 300-600

Cortisol

12.2 7-10 (7am)

Cortisol2.2 3-6 (12pm)

Cortisol1.9 2-5 (5pm)

Cortisol

0.9 <1.5 (10pm)

Epi 29.4 8-12

NE 96.5 30-55

DA 130.6 125-175

Serotonin 162.0 175-225

GABA 22.4 1.5-4.0

Glutamate 13.5 10-25

PEA 300.0 175-350

Histamine 28.0 10-25

Early stage:

Cortisol shows signs of stress

Serotonin drops

Epi, NE elevated

GABA increases to compensate

Intervention:

Reduce neurologic stress due

to NE, Epi

Support 5-HT & GABA

EARLY CHRONIC STRESS RESPONSE

Desensitized Receptors

MID-STAGE CHRONIC STRESS RESPONSE

Hypothalamus

Pituitary

Adrenal CortexAdrenal

Medulla

Cortisol

DHEA

Epinephrine

Norepinephrine

CRF

ACTH

Cortisol

Inhibitory

Feedback

LC (NE)

Norepinephrine

Mid-stage depletionDecreased cortisol & EpiIncreased DHEA & NorepiDecreased serotonin often with increases in GABA and glycineResults in: Constant stimulation of the stress response cycle CRF, ACTH, DHEA & NESerotonin starts to dropCortisol and epi levels stay low (fatigue, memory issues and brain fog)Cortisol can have burst of output (membrane instability) causing symptoms of anxiety and insomniaConstant stimulation of cortisol receptors in hypothalamus and and Locus ceruleus Desensitization of receptorsStress cycle cannot be shut off; HPA axis overdrive continues

Case 1 Case 2

Early Stage Mid-stage Optimal Range

DHEA 452.3 853.2 300-600

Cortisol ng/ml

6.2 2.1 7-10 (7am)

Cortisol ng/ml

3.2 1.5 3-6 (12pm)Cortisol ng/ml 1.9 1.8 2-5 (5pm)

Cortisol ng/ml

0.9 1.0 <1.5 (10pm)

Epi 29.4 1.3 8-12

NE 96.5 94.2 30-55

DA 130.6 255.8 125-175

5-HT 162.0 52.8 175-225

GABA 22.4 7.3 1.5-4.0

Glutm 13.5 56.2 10-25

PEA 300.0 734.2 175-350

HA 28.0 18.2 10-25

Cortisol falls

DHEA rises

Serotonin falls

DA, NE rise

Epi falls

GABA rises to “compensate”

MID-STAGE CHRONIC STRESS RESPONSE

Desensitized Receptors

LATE CHRONIC STRESS RESPONSE

Hypothalamus

Pituitary

Adrenal CortexAdrenal

Medulla

Cortisol

DHEA

Epinephrine

Norepinephrine

CRF

ACTH

Cortisol

Inhibitory

Feedback

LC (NE)

Norepinephrine

Late stage, aka “burnout”Decreased cortisol, Epi, NE, DHEA and serotonin; eventually GABA and glycine drop as well

It has also been reported that inflammatory cytokines (TNF-α , IL-1 and IL-6) also increase CRH

Prolong HPA activation suppresses growth factor

Pt 1 Pt 2 Pt 3

Early Stage Mid-stage Late

Stage

DHEA 452.3 853.2 123.3

Cortisolng/ml

6.2 2.1 1.5

Cortisolng/ml

3.2 1.5 0.9Cortisolng/ml 1.9 1.8 0.8

Cortisolng/ml

0.9 1.0 0.5

Epi 29.4 1.3 1.8

NE 731.7 94.2 22.3

DA 130.6 255.8 99.4

5-HT 162.0 52.8 67.8

GABA 133.0 7.3 9.2

Glutm 13.5 56.2 63.1

PEA 300.0 734.2 324.5

HA 28.0 18.2 9.5

DHEA

Cortisol

Epi, NE, DA

Serotonin

GABA may be high or fall

Glutamate rises

LATE CHRONIC STRESS RESPONSE

CLINICAL SYMPTOMS OF ADRENAL BURNOUT

Cognitive Impairment

Fatigue

Poor sleep

Depression

Sugar craving

Hypoglycemia

Low blood pressure

Impaired Immunity

Irritability

Digestive disturbances

Muscle pains Joint pains Secondary glandular

imbalances: Thyroid PMS Menopausal symptoms Fertility

NEEDS TO SERVE AS STARTING POINT

FOR INTERVENTION

THE NERVOUS SYSTEM:

THEALPHA & OMEGA

VAT 2 DOO ?

URINARY NEUROTRANSMITTER TESTING USES

Identify imbalances that may contribute to a clinical condition

Guide treatment selection

Monitor treatment effectiveness

Urinary neurotransmitter testing can be used to identify imbalances that may contribute to a clinical condition, to guide treatment decisions, and to monitor treatment effectiveness. The following series of slides will demonstrate these concepts with examples from current literature.

Aggression Depression ADD/ADHD Parkinson’s Migraines Insomnia OCD GI disorders Epilepsy

Compulsive behavior Gambling Drug Use Overeating

Hormone dysfunction Bulemia/Anorexia Anxiety/Panic Chronic pain Cancer Autoimmune Disease

NEUROTRANSMITTER IMBALANCE

THE NEUROMODULATION METHOD

Step 1

Step 2

Step

3

Test:

Neurological

Endocrine

Immunology

NeuroModulation:

Treatment Protocol

Retest:

Track

Adjust

Justify

URINARY TESTS AVAILABLE

Inhibitory Neurotransmitters

Excitatory Neurotransmitters

Both Excitatory and Inhibitory

GABASerotoninTaurine

Agmatine

GlutamateEpi

NorepiPEA

HistamineAspartate

DopamineGlycine

Glutamine

Currently, there are several tests available to determine urinary neurotransmitter levels; however, optimal ranges for these neurotransmitters have yet to be determined empirically. This slide lists the inhibitory and excitatory neurotransmitters that can be measured in the urine. The following series of slides provides a summary of the physical manifestations of alterations in neurotransmitter levels as detected by urine testing.

OPTIMAL RANGES FOR URINARY

NEUROTRANSMITTERS

• Spot urine collected 2-3 hours after rising.

• Ranges are reported in µg/gCR.1

Epi 8-12NE 30-55

Dopa 125-175Sero 175-225

Glycine 200-400Taurine 150-300GABA 1.5-4.0

1Data on file, NeuroScience, Inc. 2006.

Glutamine 150-400

Glutamate 10-25

Aspartic Acid 20-40

PEA 175-350

Histamine 10-25

Agmatine 1-2

While the optimal ranges for urinary neurotransmitter levels have yet to be established, some target ranges have been suggested based on data from 300-400 healthy males and females, who were 25-35 years old without clinical complaints, and who were not on any medications.1

The next series of slides provides a summary of some physical manifestations resulting from the alterations of neurotransmitter levels as detected by urine testing.

1 Data on file, NeuroScience, Inc. 2006.

URINARY GLUTAMATE LEVELS

High levels

Anxiousness

Depression

Huntington’s disease

Lou Gehrig’s disease

Alzheimer’s disease

Seizure Disorders

Low levels Fatigue Poor memory Difficulty learning

Rev Bras Psiquiatr. 2005 Sep;27(3):243-8. Epub 2005 Oct 4.

URINARY GABA LEVELS

Physiol Rev. 2004 Jul;84(3):835-67.

Symptoms of High and Low GABA levelsSymptoms of High and Low GABA levels

Low levels High levels

InsomniaFatigue

Restlessness or hyperactivity

Anxiety/panic attacksSeizuresIrritability

Bi-polar/maniaLow impulse control

Reduced inhibitionAnxiety

InsomniaPanic

Elevated urinary GABA is correlated with elevated excitatory neurotransmitter levels. High GABA levels are often seen in those with anxiety and insomnia. Panic is an excitatory symptom because a person panicking has high levels of excitatory neurotransmitters and GABA rises in response. A person suffering from fatigue often has low GABA levels, especially if they have depleted all neurotransmitters in their body.

URINARY GLYCINE LEVELS

High levels

Anxiousness

Depression

Stress related disorders

Autism

ADD/ADHD

Curr Med Chem. 2000 Feb;7(2):199-209.

Can also modulate pain

-- especially in

spinal cord)

URINARY SEROTONIN LEVELS

Low levels observed in:

Anxiousness

Fatigue

Sleep problems

Uncontrolled appetite/cravings

Migraine headaches

Premenstrual syndrome

Depression* (be careful)

High levels observed in: Hyperthermia Shaking Teeth chattering

http://www.acnp.org/g4/GN401000045/CH.html

URINARY PEA LEVELS

Low levels

Depression

Fatigue

Cognitive dysfunction

ADHD

Autism

High levels Schizophrenia Phenylketonuria Insomnia Mental stress Migraines

URINARY HISTAMINE LEVELS

Low levels

Depression

Fatigue

Antihistamine use

L-dopa therapy

High levels Active allergy or

inflammation Stress Serotonin depletion Restlessness Sleep disorders Cigarette use

URINARY DOPAMINE LEVELS

Low levels Attention difficulties Hyperactivity Memory deficits Increased motor

movement (Parkinson’s-like)

Poor fine motor control High soy intake Cravings Addictions

High levels Paranoia Stress ADD/ADHD Autism (high activity)

Initially high, later low Addictions (blunted

activity)

Physiol Rev. 1998 Jan;78(1):189-225.

URINARY NOREPINEPHRINE LEVELS Low levels

Poor memory

Reduced alertness

Somnolence

Fatigue/lethargy

Depression

Lack of interest

High levels Aggression Anxiety/Panic Increased emotionality Mania Hypertension Vasomotor Symptoms

of Perimenopause, Menopause and PMS

High levels of norepinephrine have been found in patients suffering from vasomotor symptoms of perimenopause, menopause and PMS. It is thought that this association is really a result of the level of NE relative to the level of serotonin.

Blum, I. et al. Neuropsychobiology. 2004;50:10-15.De Sloover Koch Y, Ernst ME. Ann Pharmacother. 2004;38:1293-1296. Fitzpatrick LA. Mayo Clin Proc. 2004;79:735-737.Notelovitz M. Mayo Clin Proc. 2004;79:S8-S13. Shanafelt TD et al. Mayo Clin Proc. 2002;77:1207-1218.

URINARY EPINEPHRINE LEVELS

Low levels

Poor concentration

Adrenal insufficiency

Chronic stress

Decreased metabolism

Fatigue

High levels Anxiety Insomnia Stress Hypertension Hyperactivity

IDENTIFY IMBALANCES

Low urinary dopamine and serotonin levels were correlated with depression in breast cancer patients.1

Children with ADHD with or without anxiety may have increased noradrenergic activity when compared to children without ADHD.2

1M Hernandez-Reif, G Ironson, T Field, et al. J Psychosom Res. 2004;57:45-52.

In this study, urinary NE, EPI, dopamine and serotonin levels were measured in breast cancer patients with and without massage therapy treatment three times per week to enhance mood and reduce stress. The researchers found that the long-term effects of massage therapy included increased urinary dopamine and serotonin levels in women who reported reduced depression and hostility.1

Children with attention-deficit hyperactivity disorder (ADHD) with and without anxiety were asked to complete a series of mentally stressful tasks. Urinary norepinephrine and epinephrine levels were measured during the 2-hour collection period. The researchers found that children with ADHD regardless of comorbid anxiety excreted higher levels of NE metabolites than children without ADHD, suggesting that the tonic activity of the noradrenergic system may be higher in children with ADHD. In addition, children with ADHD and anxiety excreted more EPI than children with ADHD without anxiety, suggesting that children with ADHD and anxiety may be differentiated from children without anxiety using the adrenergic system.2

1M Hernandez-Reif, G Ironson, T Field, et al. 2004. Breast cancer patients have improved immune and neuroendocrine functions following massage therapy. J Psychosom Res. 57:45-52.2S Pliszka. 1996. Catecholamines in Attention-Deficit Hyperactivity Disorder: Current Perspectives. J. Am. Acad. Child Adolesc. Psychiatry. 35:3.

IDENTIFY IMBALANCES

1JW Hughes, L Watkins, JA Blumenthal, C Kuhn, A Sherwood. J Psychosom Res. 2004;57:353-358.

Elevated levels of urinary NE were associated with depression and

anxiety in middle-aged women1

Values of NE24 for

women with BDI scores

>10 and <10

150.0000

200.0000

250.0000

300.0000

< 10 >10

NE24

mg/m2

Beck Depression Inventory Scores

In this study, self-reported symptoms of depression and anxiety were measured in middle-aged women. Depression was assessed using the Beck Depression Inventory and anxiety was assessed by the state anxiety portion of the Spielberger State-Trait Anxiety Inventory. Twenty-four hour urine samples were collected and assayed for NE and EPI. The researchers found that increased NE excretion was correlated with higher levels of depression and state anxiety and that depression and anxiety symptoms were unrelated to urinary EPI excretion.1

1JW Hughes, L Watkins, JA Blumenthal, C Kuhn, A Sherwood. 2004. Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom Res. 57:353-358.

IDENTIFY IMBALANCES

Table 1. PTSD and Depressive Symptoms in the PTSD GroupsaTable 1. PTSD and Depressive Symptoms in the PTSD GroupsaTable 1. PTSD and Depressive Symptoms in the PTSD GroupsaTable 1. PTSD and Depressive Symptoms in the PTSD Groupsa

Rating Scale Range of Scores Inpatients Outpatients

Figley PTSD 4 - 48 30.9 + 10.4 22.4 + 10.7

IES total 7 - 61 40.4 + 13.1b 22.1 + 17.7

SubscalesSubscalesSubscalesSubscales

Intrusive 3 - 33 22.8 + 8.0c 11.6 + 8.7

Avoidance 1 - 38 18.1 + 7.4 10.5 + 12.1

HDRS 7 - 44 21.1 + 11.8 18.0 + 8.0

a Results are expressed as mean + SD; b t = 2.6; df = 18; p = < 0.125; c t = 2.9; df = 18; p = < 0.008

† Due to missing data, only 14 (instead of 19) subjects were used in correlational analysis between catecholamine measures and Figley scores.

*p < .0125 (When Bonferroni corrections are used, only results occurring with a probability of .0125 or less are considered statistically significant; ** p< .02; *** p < .05.

Urinary dopamine and norepinephrine, but not epinephrine

levels, significantly correlated with severity of post-traumatic

stress disorder symptoms1 in male veterans.

1 R Yehuda, S Southwick, EL Giller, X Ma , JW Mason. J Nerv Ment Dis. 1992;180(5):321-5.

This study examined both in- and out-patients with PTSD as well as control patients. The investigators found that inpatients had significantly higher 24-hour urinary catecholamine excretion than outpatients or controls. However, PTSD patients (in- and out-patients) demonstrated elevated dopamine and norepinephrine excretion.

Table 1 shows that inpatients had more symptoms of PTSD than outpatients according to both the Figley PTSD interview, which assesses intrusive, avoidant and hyperarousal symptoms, and the Impact of Event Scale (IES). Inpatients were also more intrusive than outpatients. Depression levels did not vary between in and out house patients.

URINARY NEUROTRANSMITTER MEASUREMENTS HAVE

MULTIPLE BENEFITS

Non-invasive, quantitative nervous system analysis

Urinary NT levels correlate with CNS levels

Urinary NT levels correlate with clinical conditions

Urinary NT testing is covered by insurance

IDENTIFY URINARY NT LEVELS CORRELATE WITH CNS NT

LEVELS IMBALANCES

IDENTIFY URINARY NOREPINEPHRINE CORRELATES WITH SEVERITY OF DEPRESSION

URINARY P.E.A. LEVELS CORRELATED WITH RESPONSE

TO METHYLPHENIDATE

SUMMARY

Given the Number of Clinical Conditions Associated with Neurotransmitter Imbalances, Biomarkers that Assist in the Evaluation and Treatment of Neurotransmitter Abnormalities are Needed

SUMMARY

The complex nature of interactions between the nervous system, the immune system and the endocrine system is the foundation upon which complex human behavior (physiological and pathological) is built

Mental Health

Stress Tolerance

Good Cognitive Function

Balanced Immunity

Balanced Endocrine Function

RESEARCH IMPLIES THAT BALANCED NEUROTRANSMITTER FUNCTION IS

IMPORTANT FOR:

What They Are Not

Urinary Neurotransmitter Levels

*Not a diagnostic test*Similar symptoms do not result in uniform urinary NT levels from one

person to the next

*Patterns are seen but must be correlated with clinical picture

SUMMARY

URINARY NEUROTRANSMITTER TESTING USES

Identify imbalances that may contribute to a clinical condition

Guide treatment selection

Monitor treatment effectiveness

Urinary neurotransmitter testing can be used to identify imbalances that may contribute to a clinical condition, to guide treatment decisions, and to monitor treatment effectiveness. The following series of slides will demonstrate these concepts with examples from current literature.

SUMMARY

We cannot purport to treat these complex mechanism simply nor should we intervene blindly (no excuse for this in the 21st century)

Thank you

for your time

& attention

Questions?